title: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression.
abstract: Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.forename: Izumi
authors.initials: I
authors.lastname: Yuzawa
authors.forename: Ergin
authors.initials: E
authors.lastname: Dilekoz
authors.forename: Anne
authors.initials: A
authors.lastname: Joutel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D046589:CADASIL / Q000235:genetics* / Q000503:physiopathology; D013181:Cortical Spreading Depression / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch